Chromans and thiochromans with phenylethynyl substituents at the 7-position having retinold-like biological activity

ABSTRACT

Novel compounds of the formula ##STR1## where X is S, O; R 1  -R 5  are hydrogen or lower alkyl; R 6  is lower alkyl, lower alkenyl, lower cycloalkyl having 1 to 6 carbons, or halogen; A is lower branched chain alkyl having 2 to 6 carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, (CH 2 ) n  where n is 0-5; and B is hydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR 8 , COONR 9  R 10 , --CH 2  OH, CH 2  OR 11 , CH 2  OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13  O, --COR&#34;, CR&#34;(OR 12 ) 2 , or CR&#34;OR 13  O, where R&#34; is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8  is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8  is phenyl or lower alkylphenyl, R 9  and R 10  independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl or lower alkylphenyl, R 11  is lower alkyl, phenyl or lower alkylphenyl, R 12  is lower alkyl, R 13  is divalent alkyl radical of 2-5 carbons, have retinoic acid like activity.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of application Ser. No. 07/655,524filed on Feb. 13, 1991, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to novel compounds which have retinoicacid-like biological activity. More specifically, the present inventionrelates to compounds having an ethynyl benzoic acid portion and a secondportion which is a 2-and/or 4-substituted thiochromanyl, or chromanylgroup. The acid function may also be converted to an alcohol, aldehydeor ketone, or derivatives thereof, or may be reduced to --CH₃.

2. Related Art

European Patent Application 176034A (published Apr. 2, 1986) disclosestetrahydronaphtalene compounds having an ethynylbenzoic group. U.S. Pat.No. 4,739,098 discloses compounds wherein three olefinic units from theacid-containing moiety of retinoic acid are replaced by an ethynylphenylfunctionality. These compound have retinoic acid-like biologicalactivity.

U.S. Pat. No. 4,810,804 (issued on Mar. 7, 1989) based on an applicationof the same inventor and assigned to the same assignee as the presentapplication, discloses such disubstituted acetylene compounds whereinone of the substituents of the acetylene (ethyne) group is a substitutedphenyl group, and the second substituent is a substituted orunsubstituted 6-chromanyl, 6-thiochromanyl or 6-tetrahydroquinolinylgroup. The compounds disclosed and claimed in U.S. Pat. No. 4,810,804have retinoic acid-like biological activity.

Several co-pending applications of the present inventor, whichapplications are assigned to the assignee of the present application,are directed to further types of disubstituted acetylene compoundswherein one substituent of the acetylene (ethyne) moiety is asubstituted phenyl or a substituted heteroaryl group, and the othersubstituent is a substituted or unsubstituted 6-chromanyl,6-thiochromanyl or 6-tetrahydroquinolinyl group. The disubstitutedacetylene compounds described and claimed in the aforesaid co-pendingapplications have significant retinoic acid-like activity.

A published European patent application of the present applicant(Publication No. 0284288, published on Sep. 28, 1988) describescompounds having retinoic acid like activity which are 4,4 disubstitutedchroman-6-yl, 4,4 disubstituted--thiochroman-6-yl acetylenes alsosubstituted by a substituted heteroaryl group.

Retinoic acid-like activity has been generally recognized in the art tobe associated with useful biological activity. Specifically, compoundshaving retinoic acid-like activity are useful as regulators of cellproliferation and differentiation, and particularly as agents fortreating dermatoses, such as acne, Darier's disease, psoriasis,icthyosis, eczema, atopic dermatitis and epithelial cancers, fortreating arthritic diseases and other immunological disorders (e.g.lupus erythematosus) for promoting wound healing, for treating dry eyesyndrome and for reversing and preventing the effects of sun damage toskin.

With respect to the synthetic processes of the present invention whichinvolve either the formation of an acetylenic (ethynyl) function in thecompounds of the invention, or the coupling of the compounds of theinvention which already have the ethynyl function with a halogensubstituted phenyl group, the following articles comprise backgroundinformation: A General Synthesis of Terminal and Internal Arylalkynes bythe Palladium-Catalyzed Reaction of Alkynylzinc Reagents with ArylHalides by Anthony O. King and Ei-ichi Negishi, J. Org. Chem. 43 1978 p358; Conversion of Methyl Ketones into Terminal Acetylenes and(E)-Trisubstituted Olefins of Terpenoid Origin by Ei-ichi, Anthony O.King, and William L. Klima, J. Org. Chem. 45 1980 p.2526, and AConvenient Synthesis of Ethynylarenes and Diethynylarenes by S.Takahashi, Y. Kuroyama, K. Sonogashira, N. Hagihara, Synthesis 1980 p627-630.

SUMMARY OF THE INVENTION

This invention covers compounds of Formula 1 ##STR2## wherein X is S, O;R₁ -R₅ are hydrogen or lower alkyl; R₆ is lower alkyl, lower alkenyl,lower cycloalkyl having 1 to 6 carbons, or halogen; A is lower branchedchain alkyl having 2 to 6 carbons, cycloalkyl having 3 to 6 carbons,alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2to 6 carbons and 1 or 2 triple bonds, (CH₂)_(n) where n is 0-5; B ishydrogen, COOH or a pharmaceutically acceptable salt thereof, COOR₈,COONR₉ R₁₀, --CH₂ OH, CH₂ OR₁₁, CH₂ OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃ O,--COR", CR"(OR₁₂)₂, or CR"OR₁₃ O, where R" is an alkyl, cycloalkyl oralkenyl group containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl orlower alkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl groupof 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenylor lower alkylphenyl, R₁₁ is lower alkyl, phenyl or lower alkylphenyl,R₁₂ is lower alkyl, R₁₃ is divalent alkyl radical of 2-5 carbons.

In a second aspect, this invention relates to the use of the compoundsof Formula 1 for treating dermatoses, such as ache, Darier's disease,psoriasis, icthyosis, eczema, atopic dermatitis and epithelial cancers.These compounds are also useful in the treatment of arthritic diseasesand other immunological disorders (e.g. lupus erythematosus), inpromoting wound healing, in treating dry eye syndrome and in reversingthe effects of sun damage to skin.

This invention also relates to a pharmaceutical formulation comprising acompound of Formula 1 in admixture with a pharmaceutically acceptableexcipient.

In another aspect, this invention relates to the process for making acompound of Formula 1 which process comprises reacting a compound ofFormula 2 with a compound of Formula 3 in the presence of cuprous iodideand Pd(PQ₃)₂ Cl₂ (Q is phenyl) or a similar complex ##STR3## where R₁-R₆ are the same as described above, X' is a halogen, preferably I; andA is the same as defined above; and B is H, or a protected acid,alcohol, aldehyde or ketone, giving the corresponding compound ofFormula 1; or to the process of making a compound of Formula 1 whichconsists of reacting a zinc salt of Formula 4 with a compound of Formula3 in the presence of Pd(PQ₃)₄ (Q is phenyl) or a similar complex.##STR4## where R₁ -R₆, and X, are the same as defined above, giving thecorresponding compound of Formula 1; or homologating a compound of theFormula 5 ##STR5## where n is 0-4 to give an acid of Formula 1; orconverting an acid of Formula 1 to a salt; or

forming an acid addition salt;

converting an acid of Formula 1 to an ester; or

converting an acid of Formula 1 to an amide; or

reducing an acid of Formula 1 to an alcohol or aldehyde; or

converting an alcohol of Formula 1 to an ether or ester; or

oxidizing an alcohol of Formula 1 to an aldehyde; or

converting an aldehyde of Formula 1 to an acetal; or

converting a ketone of Formula 1 to a ketal.

GENERAL EMBODIMENTS

Definitions

The term "ester" as used here refers to and covers any compound fallingwithin the definition of that term as classically used in organicchemistry. Where B (of Formula 1) is --COOH, this term covers theproducts derived from treatment of this function with alcohols,preferably with aliphatic alcohols having 1-6 carbons. Where the esteris derived from compounds where B is --CH₂ OH, this term coverscompounds of the formula --CH₂ OOCR where R is any substituted orunsubstituted aliphatic, aromatic or aliphatic-aromatic group,preferably with 1-6 carbons in the aliphatic portions.

Preferred esters are derived from the saturated aliphatic alcohols oracids of ten or fewer carbon atoms or the cyclic or saturated aliphaticcyclic alcohols and acids of 5 to 10 carbon atoms. Particularlypreferred aliphatic esters are those derived from lower alkyl acids oralcohols. Here, and where ever else used, lower alkyl means having 1-6carbon atoms and includes straight as well as branched chain alkylgroups. Also preferred are the phenyl or lower alkylphenyl esters.

Amide has the meaning classically accorded that term in organicchemistry. In this instance it includes the unsubstituted amides and allaliphatic and aromatic mono-and di-substituted amides. Preferred amidesare the mono- and di-substituted amides derived from the saturatedaliphatic radicals of ten or fewer carbon atoms or the cyclic orsaturated aliphatic-cyclic radicals of 5 to 10 carbon atoms.Particularly preferred amides are those derived from lower alkyl amines.Also preferred are mono- and di-substituted amides derived from thephenyl or lower alkylphenyl amines. Unsubstituted amides are alsopreferred.

Acetals and ketals include the radicals of the formula --CK where K is(--OR)₂. Here, R is lower alkyl. Also, K may be --OR₁ O-- where R₁ islower alkyl of 2-5 carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compound ofthis invention having a functionality capable of forming such salt, forexample an acid or an amine functionality. A pharmaceutically acceptablesalt may be any salt which retains the activity of the parent compoundand does not impart any deleterious or untoward effect on the subject towhich it is administered and in the context in which it is administered.

Such a salt may be derived from any organic or inorganic acid or base.The salt may be a mono or polyvalent ion. Of particular interest wherethe acid function is concerned are the inorganic ions, sodium,potassium, calcium, and magnesium. Organic amine salts may be made withamines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Where there is a nitrogensufficiently basic as to be capable of forming acid addition salts, suchmay be formed with any inorganic or organic acids or alkylating agentsuch as methyl iodide. Preferred salts are those formed with inorganicacids such as hydrochloric acid, sulfuric acid or phosphoric acid. Anyof a number of simple organic acids such as mono-, di- or tri-acid mayalso be used.

The preferred compounds of this invention are those where the ethynylgroup and the B group are attached to the 1 and 4 positions respectivelyof a benzene ring (i.e. where the phenyl moiety of the compound is parasubstituted) A is (CH₂)_(n) and n is 0; and B is --COOH, an alkali metalsalt or organic amine salt, or a lower alkyl ester thereof, or --CH₂ OHand the lower alkyl esters and ethers thereof, (formed with a loweralkanol) or --CHO and acetal derivatives thereof. The more preferredcompounds shown in Formula 6 are:

ethyl 4-(4,4-dimethyl-7-thiochromanyl)-ethynyl-benzoate (Compound 1,X═S, R₃ ═H, R₄ ═H, R₅ ═H, R"═C₂ H₅);

4-[(4-4-dimethyl-7-thiochromanyl)-ethynyl]-benzoic acid (Compound 2,X═S, R₃ ═H, R₄ ═H, R₅ ═H, R"═H);

ethyl 4-(2,2,4,4-tetramethyl-7-thiochromanyl)-ethynylbenzoate (Compound3, X═S, R₃ ═H, R₄ ═CH₃, R₅ ═CH₃, R"═C₂ H₅);

ethyl-4-(2,2,4,4-tetramethyl-7-chromanyl)-ethynylbenzoate (Compound 4,X═O, R₃ ═H, R₄ ═CH₃, R₅ ═CH₃, R"═C₂ H₅).

4-(2,2,4,4-tetramethyl-7-thiochromanyl)-ethynyl benzoic acid (Compound49, X═S, R₃ ═H, R₄ ═CH₃, R₅ ═CH₃, R"═H).

4-(2,2,4,4-tetramethyl-7-chromanyl)-ethynyl benzoic acid (Compound 50,X═O, R₃ ═H, R₄ ═CH₃, R₅ ═CH₃, R"═H). ##STR6##

The compounds of this invention may be administered systemically ortopically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and similar considerations.

In the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic acne, oral administration may also be used. Any commontopical formulation such as a solution, suspension, gel, ointment, orsalve and the like may be used. Preparation of such topical formulationsare well described in the art of pharmaceutical formulations asexemplified, for example, Remington's Pharmaceutical Science, Edition17, Mack Publishing Company, Easton, Pa. For topical application, thesecompounds could also be administered as a powder or spray, particularlyin aerosol form.

If the drug is to be administered systemically, it may be confected as apowder, pill, tablet or the like, or as a syrup or elixir for oraladministration. For intravenous or intraperitoneal administration, thecompound will be prepared as a solution or suspension capable of beingadministered by injection. In certain cases, it may be useful toformulate these compounds in suppository form or as an extended releaseformulation for deposit under the skin or intermuscular injection.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness, providing protectionagainst light; other medications for treating dermatoses, preventinginfection, reducing irritation, inflammation and the like.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoic acid-like compounds will beeffected by administration of the therapeutically effective dose of oneor more compounds of the instant invention. A therapeutic concentrationwill be that concentration which effects reduction of the particularcondition, or retards its expansion. In certain instances, the drugpotentially could be used in a prophylactic manner to prevent onset of aparticular condition. A given therapeutic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, a given therapeutic concentration will bebest determined at the time and place through routine experimentation.However, it is anticipated that in the treatment of, for example, acne,or other such dermatoses, that a formulation containing between 0.001and 5 percent by weight, preferably about 0.01 to 1% will usuallyconstitute a therapeutically effective concentration. If administeredsystemically, an amount between 0.01 and 100 mg per kg body weight perday, but preferably about 0.1 to 10 mg/kg, will effect a therapeuticresult in most instances.

The retionic acid like activity of these compounds was confirmed throughthe classic measure of retionic acid activity involving the effects ofretionic acid on ornithine decarboxylase. The original work on thecorrelation between retinoic acid and decrease in cell proliferation wasdone by Verma & Boutwell, Cancer Research, 1977, 37, 2196-2201. Thatreference discloses that ornithine decarboxylase (ODC) activityincreased precedent to polyamine biosynthesis. It has been establishedelsewhere that increases in polyamine synthesis can be correlated orassociated with cellular proliferation. Thus, if ODC activity could beinhibited, cell hyperproliferation could be modulated. Although allcauses for ODC activity increase are unknown, it is known that12-0-tetradecanoylphorbol-13-acetate (TPA) induces ODC activity.Retinoic acid inhibits this induction of ODC activity by TPA. Thecompounds of this invention also inhibit TPA induction of ODC asdemonstrated by an assay essentially following the procedure set out inCancer Res., 35: 1662-1670, 1975.

By way of example of retinoic acid-like activity it is noted that in theassay conducted essentially in accordance with the method of Verma &Boutwell, ibid, the following examples of the preferred compounds of thepresent invention (Compounds 1, 2, 3 and 4) attained an 80% inhibitionof TPA induced ODC activity at the following concentrations (IC₈₀):

    ______________________________________                                        Compound     IC.sub.80 conc (nmols)                                           ______________________________________                                        1            0.81                                                             2            1.54                                                             3            1.23                                                             4            0.35                                                             ______________________________________                                    

SPECIFIC EMBODIMENTS

The compounds of this invention can be made by a number of differentsynthetic chemical pathways. To illustrate this invention, there is hereoutlined a series of steps which have been proven to provide thecompounds of Formula 1 when such synthesis is followed in fact and inspirit. The synthetic chemist will readily appreciate that theconditions set out here are specific embodiments which can begeneralized to any and all of the compounds represented by Formula 1.Furthermore, the synthetic chemist will readily appreciate that theherein described synthetic steps may be varied and or adjusted by thoseskilled in the art without departing from the scope and spirit of theinvention.

Compounds of Formula 1 where X is --S-- and R₄ and R₅ are hydrogen orlower alkyl, are prepared as per Reaction Scheme 1 ##STR7##

In Reaction Scheme 1, R₁ -R₅ are hydrogen or a lower alkyl group, R₆ isdefined as above in connection with Formula 1, A is lower branched chainalkyl having 2 to 6 carbons, cycloalkyl having 3 to 6 carbons, alkenylhaving 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6carbons and 1 or 2 triple bonds, (CH₂)_(n) where n is 0-5 and B is H, ora protected acid, alcohol, aldehyde or ketone. X' is Cl, Br or I when nis 0 but preferably is Br or I when n is 1-5.

Compounds of Formula 1 where X is oxygen and R₄ and R₅ are hydrogen orlower alkyl, are prepared as per Reaction Scheme 2. ##STR8##

In Reaction Scheme 2 the definitions of R₁ -R₆, A, B and X' are the sameas in Reaction Scheme 1.

A general description of the synthetic steps outlined in ReactionSchemes 1 and 2 is as follows.

In Reaction Scheme 1 the 3-bromo-thiophenol (Compound 5) is acylatedwith an acylating agent, such as an acid chloride (Compound 6) derivedfrom an appropriately substituted acrylic acid. The acylation isconducted in an inert solvent (such as tetrahydrofuran) in the presenceof strong base (for example sodium hydrdride). The resulting thioester(Compound 7) which contains the olefinic bond of the acrylic acid moietyis ring closed in the presence of a Friedel Crafts type catalyst (suchas aluminum chloride) by stirring in a suitable solvent such asmethylene chloride. The resulting 2-oxo-7-bromothiochroman (Compound 8)is usually isolated in crystalline form.

The R₄ and/or R₅ substituents are introduced by treating the2-oxo-7-bromo-thiochroman (Compound 8) with a Grignard reagent in thepresence of CeCl₃, bearing the alkyl substituents R₄ and R₅ (such asmethylmagnesium bromide when R₄ and R₅ are methyl). When the Grignardreagent (such as methylmagnesium bromide) is in excess, the thiochromanring is opened and the tertiary alcohol derivative of the 3-bromothiophenol (Compound 9) is formed.

Ring closure of the thiophenol derivative (Compound 9) which has thedesired R₁, R₂, R₃, R₄ and R₅ substituents, is affected by heating inacidic conditions, preferably by heating Compound 9 in aqueous acid. Theresulting 7-bromothiochroman which bears the desired alkyl (or hydrogen)substituents, R₁, R₂, R₃, R₄ and R₅ is shown as Compound 10 in ReactionScheme 1.

To introduce the acetylene (ethyne) portion into the molecule, thesubstituted 7-bromothiochroman (Compound 10) is reacted withtrimethylsilylacetylene in the presence of cuprous iodide and a suitablecatalyst, typically having the formula Pd(PQ₃)₂ Cl₂ (Q is phenyl). Thereaction is typically conducted in the presence ofbis(triphenylphosphine) palladium (II) chloride catalyst and an acidacceptor (such as triethylamine) under an inert gas (argon) atmosphere,by heating in a sealed tube. The resulting7-trimethylsilylethynylthiochroman is shown as Compound 11 in ReactionScheme 1.

As is shown on Reaction Scheme 1, the trimethylsilyl moiety is removedfrom the 7-trimethylsilylethynyl-thiochroman (Compound 11) in the nextsynthetic step, to provide the ring substituted 7-ethynyl-thiochromanderivative (Compound 12). The latter reaction is conducted under basicconditions, preferably under an inert gas atmosphere.

In order to introduce the phenyl or substituted phenyl substituent onthe acetylene (ethyne) portion of Compound 12, Compound 12 is coupledwith the reagent X'--Q--A--B (Formula 3, Q is a di- or multi-substitutedphenyl residue) where the symbols A, X' and B have the same meaning asdefined in connection with Formula 3. In other words, the phenyl orsubstituted phenyl substituent is introduced into the7-ethynyl-thiochroman (Compound 12) by reacting the latter with ahalogen substituted phenyl compound (Formula 3) in which the benzenenucleus either has the desired substituent [A-B] or wherein the actualsubstituent A-B can be readily converted to the desired substituent bymeans of organic reactions well known in the art.

Coupling of the 7-ethynyl-thiochroman (Compound 12) with the reagentX'--Q--A--B is affected directly in the presence of cuprous iodide, asuitable catalyst, typically of the formula Pd(PQ₃)₂ Cl₂ and an acidacceptor, such as triethylamine, by heating in a sealed tube under aninert gas (argon) atmosphere.

The resulting disubstituted acetylene compound (Compound 14) may be thetarget compound made in accordance with the invention, or maybe readilyconverted into the target compound by such steps as salt formation,esterification, deesterification, homologation, amide formation and thelike. These steps are further discussed below.

Compound 14 may also be obtained by first converting the7-ethynyl-thiochroman derivative (Compound 12) into a correspondingmetal salt, such as a zinc salt, (Compound 13) and thereafter couplingthe salt (Compound 13) with the reagent X'--Q--A--B (Formula 3 Q isphenyl or substituted phenyl residue) in the presence of a catalysthaving the formula Pd(PQ₃)₄ (Q is phenyl), or similar complex.

Derivatization of Compound 14 is indicated in Reaction Scheme 1 asconversion to "homologs and derivatives" Compounds 15.

More specifically with respect to either derivatization or deblocking ofprotected functionalities in Compound 14, or with respect to thepreparation of phenyl derivatives of the formula X'--Q--A--B, (whichafter coupling either directly yield the compounds of the invention, orare readily converted into them) the following is noted.

Where a protected phenyl derivative is needed to couple with thecompounds of Formula 2 (Compounds 12 in Reaction Scheme 1), such may beprepared from their corresponding acids, alcohols, ketones or aldehydes.These starting materials, the protected acids, alcohols, aldehydes orketones, are all available from chemical manufacturers or can beprepared by published methods. Carboxylic acids are typically esterifiedby refluxing the acid in a solution of the appropriate alcohol in thepresence of an acid catalyst such as hydrogen chloride or thionylchloride. Alternatively, the carboxylic acid can be condensed with theappropriate alcohol in the presence of dicyclohexylcarbodiimide anddimethylaminopyridine. The ester is recovered and purified byconventional means. Acetals and ketals are readily made by the methoddescribed in March, "Advanced Organic Chemistry," 2nd Edition ,McGraw-Hill Book Company, p 810). Alcohols, aldehydes and ketones allmay be protected by forming respectively, ethers and esters, acetals orketals by known methods such as those described in McOmie, PlenumPublishing Press, 1973 and Protecting Groups, Ed. Greene, John Wiley &Sons, 1981.

To increase the value of n before effecting a coupling reaction, wheresuch compounds are not available from a commercial source, the phenylderivatives where B is --COOH are subjected to homologation bysuccessive treatment under Arndt-Eistert conditions or otherhomologation procedures. Alternatively, phenyl derivatives where B isdifferent from COOH, may also be homologated by appropriate procedures.The homologated acids can then be esterified by the general procedureoutlined in the preceding paragraph.

An alternative means for making compounds where A is (CH₂)_(n) n is 1-5is to subject the compounds of Formula 1, where B is an acid or otherfunction, to homologation, using the Arndt-Eistert method referred toabove, or other homologation procedures.

Compounds of Formula 1 where A is an alkenyl group having one or moredouble bonds can be made for example, by having the requisite number ofdouble bonds incorporated into the intermediate of Formula 3; that is byusing for the intermediate of Formula 3 an unsaturated aromatic compoundbearing the X' leaving group (preferably halogen) in the phenyl nucleus.4-Bromo or 4-iodo-cinnamic acid ethyl ester serve as concrete examples.Generally speaking, the compounds of Formula 3 where A is an unsaturatedcarbon chain can be obtained by synthetic schemes well known to thepracticing organic chemist; for example by Wittig and like reactions, orby introduction of a double bond by elimination of halogen from analpha-halo-phenylalkyl-carboxylic acid, ester or like carboxaldehyde.Compound of Formula 1 where the A group has a triple (acetylenic) bondcan be made by using the corresponding intermediate of Formula 3. Suchintermediate can be obtained by reactions well known in the art, forexample, by reaction of a corresponding phenyl-methyl ketone with strongbase, such as lithium diisopuopyl amide.

The acids and salts derived from Formula 1 are readily obtainable fromthe corresponding esters. Basic saponification with an alkali metal basewill provide the acid. For example, an ester of Formula 1 may bedissolved in a polar solvent such as an alkanol, preferably under aninert atmosphere at room temperature, with about a three molar excess ofbase, for example, potassium hydroxide. The solution is stirred for anextended period of time, between 15 and 20 hours, cooled, acidified andthe hydrolysate recovered by conventional means.

The amide may be formed by any appropriate amidation means known in theart from the corresponding esters or carboxylic acids. One way toprepare such compounds is to convert an acid to an acid chloride andthen treat that compound with ammonium hydroxide or an appropriateamine. For example, the acid is treated with an alcoholic base solutionsuch as ethanolic KOH (in approximately a 10% molar excess) at roomtemperature for about 30 minutes. The solvent is removed and the residuetaken up in an organic solvent such as diethyl ether, treated with adialkyl formamide and then a 10-fold excess of oxalyl chloride. This isall effected at a moderately reduced temperature between about -10degrees and +10 degrees C. The last mentioned solution is then stirredat the reduced temperature for 1-4 hours, preferably 2 hours. Solventremoval provides a residue which is taken up in an inert inorganicsolvent such as benzene, cooled to about 0 degrees C. and treated withconcentrated ammonium hydroxide. The resulting mixture is stirred at areduced temperature for 1-4 hours. The product is recovered byconventional means.

Alcohols are made by converting the corresponding acids to the acidchloride with thionyl chloride or other means (J. March "AdvancedOrganic Chemistry" 2nd Edition, McGraw-Hill Book Company), then reducingthe acid chloride with sodium borohydride (March, Ibid, pg. 1124), whichgives the corresponding alcohols. Alternatively, esters may be reducedwith lithium aluminum hydride at reduced temperatures. Alkylating thesealcohols with appropriate alky halides under Williamson reactionconditions (March, Ibid, pg. 357) gives the corresponding ethers. Thesealcohols can be converted to esters by reacting them with appropriateacids in the presence of acid catalysts or dicyclohexlcarbodiimide anddimethlaminopyridine.

Aldehydes can be prepared from the corresponding primary alcohols usingmild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.,Tetrahedron, 1978, 34, 1651).

Ketones can be prepared from an appropriate aldehyde by treating thealdehyde with an alkyl Grignard reagent or similar reagent followed byoxidation.

Acetals or ketals can be prepared from the corresponding aldehyde orketone by the method described in March, Ibid, p 810.

Compounds where B is H can be prepared from the correspondinghalogenated benzene compounds, preferably where the halogen is I.

With reference to Reaction Scheme 2, 3-bromophenol, or a 3-bromophenolsubstituted in the 4-(para) position by an alkyl substituent (R₃)(Compound 16) is acylated with an acylating agent, such as an acidchloride (Compound 6) derived from an appropriately substituted acrylicacid. In Reaction Scheme 2, just as in Reaction Scheme 1, the R₁ and R₂substituents of the target compounds are introduced through this acrylicacid derivative (Compound 6). The acylation with the acid chloride(Compound 6) is preferably conducted in the presence of a strong base(e.g. sodium hydride) in an inert solvent (such as tetrahydrofuran). Theresulting substituted phenyl-acrylate is shown in Reaction Scheme 2 asCompound 17.

The substituted phenyl-acrylate 17 is ring closed under Friedel Craftstype reaction conditions (AlCl₃ catalyst, in an inert solvent, such asmethylene chloride) to provide the 2-oxo-7-bromo-chroman compound(Compound 18) which bears, in the 4-position, the R₁ and R₂ substituentsand in the 6-position the R₃ substituent (as applicable). Just like theanalogous 2-oxo-thiochroman (Compound 8) in Reaction Scheme 1, the2-oxo-chroman 18 of Reaction Scheme 2 is treated with a Grignard reagentto introduce the R₄ and R₅ substituents. When R₄ and R₅ are methyl, theGrignard reagent is preferably methylmagnesium chloride (dissolved intetrahydrofuran, THF). A solution of Compound 18 in a suitable solvent,for example in dry diethylether is added to this Grignard reagent. Theresulting phenol containing a tertiary alcohol side chain, (that is amolecule in which the chroman ring had been opened) is shown in ReactionScheme 2 as Compound 19.

Compound 19 which already has the desired R₁, R₂, R₃, R₄ and R₅substituents, is ring closed under acidic conditions, (e.g. by heatingin aqueous sulfuric acid) to provide the chroman derivative (Compound20). To introduce the acetylene (ethyne) portion into the molecule, thesubstituted 7-bromo chroman (Compound 20) is reacted with trimethylsilylacetylene in the presence of cuprous iodide and a suitable catalyst,typically having the formula Pd(PQ₃)₂ Cl₂ (Q is phenyl), as defined forthe 7-bromo-thiochroman compound in Reaction Scheme 1. The resulting7-trimethylsilyl-ethynyl-chroman is shown as Compound 21 in ReactionScheme 2.

In Reaction Scheme 2, just as in Reaction Scheme 1, the trimethylsilylmoiety is removed from the 7-trimethylsilylethynyl-chroman (Compound 21)under basic conditions, to provide the ring substituted7-ethynyl-chroman derivative (Compound 22).

Referring still to Reaction Scheme 2, the 7-ethynyl-chroman derivative(Compound 22) may be converted into the target compounds of theinvention in synthetic steps which are analogous to the conversion of7-ethynyl-thiochromans (Compound 12) into the corresponding targetthiochroman derivatives (See Reaction Scheme 1). Briefly, Compound 22 ispreferably heated with a reagent X'--Q--A--B (Formula 3, Q is phenyl orsubstituted phenyl residue) in the presence of cuprous iodide, asuitable catalyst, typically of the formula Pd(PQ₃)₂ Cl₂ (Q is phenyl orthe like) and an acid acceptor, such as triethylamine. This couplingreaction, yields the target chroman compounds, (Compound 24) or suchderivatives which are readily converted into the target compounds byprotection, deprotection, esterification, homologation etc., as isdiscussed in connection with Reaction Scheme 1. The homologs areindicated, as a group, as Compound 25 in Reaction Scheme 2.

Alternatively, the 7-ethynyl-chroman compounds (Compound 22) may firstbe converted to the corresponding metal (zinc) salt (Compound 23) andthereafter coupled with the reagent X'--Q--A--B (Formula 3, Q is phenylor substituted phenyl residue) under conditions which are similar to theconditions described in Reaction Scheme 1 for coupling of Compounds 13with the same reagent. ##STR9## Referring to Reaction Scheme 3, thesubstituted 7-bromothiochroman (Compound 10), where one of the R₄ or R₅substituents is alkyl and the other is hydrogen, can be made by treatingthe 2-oxo-7-bromo-thiochroman (Compound 8) with a Grignard reagent. Asin Reaction Scheme 1 the 2-oxo-thiochroman (Compound 8) is subjected toan excess of Grignard reagent, bearing the alkyl substituents R₄ or R₅(such as methylmagnesium bromide when R₄ or R₅ is methyl). However, thereaction temperature is controlled and maintained at a relatively lowtemperature (such as -14 degrees C.) and the duration of the reaction iskept relatively short (0.5 hours). A hemiacetal derivative of3-bromothiophenol (Compound 26) is formed in this controlled Grignardreaction, as shown in Reaction Scheme 3. Compound 26 is converted byheating in acidic conditions, preferably with aqueous acid, to theunsaturated derivative (Compound 27). Compound 27 is reduced byhydrogenation in the presence of palladium sulfide-on-carbon catalyst atincreased pressure (approximately 30 psi). The resulting7-bromo-thiochroman which bears the desired hydrogen and alkylsubstituents R₁, R₂, R₃, R₄ and R₅ with one of R₄ or R₅ being hydrogen,is shown as Compound 10.

To obtain the 7-bromothio chroman (Compound 10), (Reaction Scheme 4)where the R₄ and R₅ substituents both are alkyl but not identical withone another, the hemiacetal derivative (Compound 26) is treated with adifferent Grignard reagent than previously used, as shown in Scheme 4.In this Grignard reaction the thiochroman ring is opened and thetertiary alcohol derivative of 3-bromo-thiophenol (Compound 9), isformed. Ring closure of the thiophenol derivative (Compound 9) which hasthe desired R₁, R₂, R₃, R₄ and R₅ substituents, is affected by heatingin acidic conditions, preferably by heating with aqueous acid. Theresulting 7-bromo thiochroman which bears the desired alkyl and hydrogensubstituents R₁, R₂, R₃, R₄ and R₅ is shown as Compound 10. ##STR10##

In Reaction Scheme 5, just as in Reaction Scheme 3, one of the R₄ or R₅substituents is alkyl and the other is hydrogen. Just like the analogous2-oxo-thiochroman (Compound 8) in Reaction Scheme 3, the 2-oxochroman(Compound 18) of Reaction Scheme 5 is treated with a Grignard reagent tointroduce the R₄ and R₅ substituents. With controlled reactiontemperature and time, the resulting hemiacetal derivative can beisolated as Compound 28, as shown in Reaction Scheme 5. Under acidicconditions, (e.g. by heating in aqueous acid) the hemiacetal (Compound28) is cyclized to form the corresponding unsaturated derivative(Compound 29). The unsaturated derivative can then be reduced using thesame conditions as described in connection with Reaction Scheme 3 forthe reduction of Compound 26, or by a more general reducing procedure.The resulting chroman derivative is shown as Compound 20 in ReactionScheme 5. ##STR11##

Referring to Reaction Scheme 6, in Compound 20 of that scheme the R₄ andR₅ substituents are alkyl but are not identical. The R₄ and R₅ alkylsubstituents are introduced by treating Compound 28 with a differentGrignard reagent than previously used, to form the tertiary alcohol(Compound 19). The tertiary alcohol (Compound 19) which already has thedesired R₁, R₂, R₃, R₄ and R₅ substituents, is ring closed under acidicconditions, as described above, to provide the chroman derivative(Compound 20).

In order to obtain the final acetylenic products where one of the R₄ orR₅ substituent is alkyl and the other is hydrogen, or where the R₄ andR₅ substituents are alkyl but not identical to one another, Compounds 10and 20 are subjected to substantially the same reaction procedures asoutlined in Reaction Scheme 1 and Reaction Scheme 2.

With reference to the compounds of Formula 1, Reaction Scheme 7illustrates an example of their synthesis when X═S and R₄ and R₅ areboth hydrogen. ##STR12##

Thus, with reference to Reaction Scheme 7, the 3-bromothiophenol(Compound 5) (which maybe alkyl substituted in the 4-position) isalkylated with Compound 30. The resulting 3-bromo phenyl sulfides(Compound 31) are ring closed under Friedel Crafts (or like) conditionsby refluxing in an inert solvent such as benzene or toluene, in thepresence of phosphorus pentoxide and phosphoric acid. The resultingthiochroman (Compound 10) made in accordance with Reaction Scheme 7 hasR₄ and R₅ as hydrogen, and preferably in accordance with this reactionscheme, R₁ and R₂ are methyl and R₃ is hydrogen.

To introduce the acetylene (ethyne) portion into the molecule, thesubstituted 7-bromothiochromane (Compound 10) is reacted withtrimethylsilyl-acetylene in the presence of cuprous iodide and asuitable catalyst, typically having the formula Pd(PQ₃)₂ Cl₂ (Q isphenyl). The reaction is typically conducted in the presence ofbis(triphenylphosphine) palladium (II) chloride catalyst, an acidacceptor, (such as triethylamine) under an inert gas (argon) atmosphere,by heating in a sealed tube. The resulting7-trimethylsilylethynylthiochroman, is shown as Compound 11 in ReactionScheme 7.

As is further shown on Reaction Scheme 7, the trimethylsilyl moiety isremoved from the 7-trimethylsilylethynyl-thiochroman (Compound 11) inthe next synthetic step, to provide the ring substituted7-ethynyl-thiochroman derivative (Compound 12). The latter reaction isconducted under basic conditions, preferably under an inert gasatmosphere.

The 7-ethynyl-thiochroman (Compound 12) can be utilized directly in thecoupling reaction set forth in Reaction Scheme 1, or prior to couplingcan be converted to the corresponding ZnCl salt, as is described above.

Turning to compounds of Formula 1 where X═O and where R₄ and R₅ are H,(that is turning to chromans substituted in the 4, and possibly in the 6position) the compounds can be made as indicated in Reaction Scheme 8.##STR13##

In Reaction Scheme 8 R₁ and R₂ are hydrogen or lower alkyl having 1 to 6carbons, and R₃ is defined as above in connection with Formula 1.

The 2-oxo-chroman (Compound 18) of Reaction Scheme 2 is reduced withlithium aluminum hydride (or by a similar reducing agent) to provide thediol (Compound 32). The primary hydroxyl group of Compound 32 isselectively mesylated over the phenolic hydroxyl, followed byintramolecular displacement of the mesylate group under basicconditions, to give a 7-bromo-chroman derivative (Compound 20) whichbears the desired alkyl substituents at R₁ and R₂ and where R₄ and R₅are both hydrogen. The acetylenic (ethyne) function is introduced intothe 4,4 disubstituted (and optionally 6-substituted) chroman Compound 20in a sequence of reaction steps which are described in Reaction Scheme 7in connection with the analogous thiochroman compounds.

As is further shown on Reaction Scheme 8 and in analogy to the reactionsequence shown on Reaction Scheme 7, the trimethylsilyl moiety isremoved from 7-trimethylsilyl-ethynyl-thiochroman (Compound 21) underbasic conditions, preferably under an inert gas atmosphere.

The 7-ethynyl-thiochroman (Compound 22) can be utilized directly in thecoupling reaction as described for Reaction Scheme 2, or prior tocoupling can be converted to the corresponding ZnCl salt as is describedabove.

SPECIFIC EXAMPLES S-(3-Bromophenyl) 3,3-dimethyl-thio acrylate (Compound33)

To an ice-bath cooled solution of 4.5 g (112.5 mmol) of sodium hydride(60% suspension in mineral oil) in 50 ml of dry THF was added slowlyunder argon a solution of 20 g (105.8 mmol) of 3-bromothiophenol in 80ml of dry THF. The mixture was stirred at 0° C. for 30 minutes and thentreated with a solution of 14 g (118 mmol) of dimethylacryloyl chloridein 30 ml of dry THF. The reaction mixture was allowed to stir at roomtemperature for 24 hours. The reaction mixture was poured onto 300 ml ofwater containing 5 ml of glacial acetic acid and the organic layer wasseparated. The aqueous layer was extracted with 2×200 ml ether. Theorganic extracts were combined and washed with 100 ml of water and 100ml of saturated NaCl solution and then dried (MgSO₄). The solvent wasremoved in vacuo and the residue was kugelrohr distilled to give thetitle compound as a pale yellow oil.

PMR (CDCl₃); & 1.90 (3H, s), 2.14 (3H, s), 6.04 (1H, s), 7.26 (1H, t,J˜7.8 Hz), 7.36 (1H, d, J˜4 Hz), 7.5 (1H, dd, J˜7.8 Hz, J˜1.7 Hz), 7.59(1H, d, J˜1.7 Hz)

4,4 Dimethyl-7-bromo-2-oxo-thiochroman (Compound 34)

To a stirred, ice cooled suspension of 20 g (150 mmol) of aluminumchloride in 250 ml of methylene chloride was added a solution of 17 g(89.5 mmol) of S-(3-bromopenyl) 3-3 dimethylthio acrylate (Compound 33)in 100 ml of methylene chloride. The mixture was stirred at roomtemperature for 24 hours and then poured nto 200 ml of an ice and brinemixture. The organic layer was separated and the aqueous layer wasextracted with 150 ml of ether. The organic extracts were combined andthen washed with water and saturated NaCl solution and dried (MgSO₄).The solvent was removed in vacuo and the residue purified by flashcolumn chromatography (silica; 2% ethyl acetate, hexanes) to give thetitle compound as a white solid.

PMR (CDCl₃); & 1.38 (6H, s), 2.65 (2H, s) 7.33 (3H, s).

5-Bromo-2-(1,1,3-trimethyl-3 hydroxy butyl)-thiophenol (Compound 35)

To 132 g (354.3 mmol) of Cerium chloride (dried under vacuum at 135° C.for 2 days) was added 200 ml of dry THF, and the suspension was stirredat room temperature for 20 hours. The reaction mixture was then cooledto 0° C. and treated with 103 ml (309 mmol) of a 3.0M solution of methylmagnesium chloride in THF. The mixture was stirred at room temperaturefor 4 hours, cooled to 0° C., and treated with a solution of 9.6 g (35.4mmol) of 4-4 dimethyl-7-bromo-2-oxo-thio-chroman (Compound 34) in 60 mlof dry THF. The reaction mixture was allowed to stir at room temperaturefor 18 hours and then poured into 200 ml of ice containing 2 ml ofsulfuric acid. The mixture was extracted with 500 ml of ether. The etherextracts were combined and washed with 300 ml of water and 300 ml ofsaturated NaCl solution and then dried (MgSO₄). The solvent was removedin vacuo to give the title compound as a pale yellow oil.

PMR (CDCl₃); & 1.08 (6H, s), 1.54 (6H, s), 2.31 (2H, s), 7.24 (1H, dd,J˜8.5 Hz, J˜2 Hz), 7.30 (1H, d, J˜8.5 Hz) 7.34, (1H, d, J˜2 Hz).

2,2,4,4 Tetramethyl-7-bromo-thiochroman (Compound 36)

A mixture of 10 g (33 mmol) of5-bromo-2-(1,1,3-trimethyl-3-hydroxybutyl) thiophenol (Compound 35) and100 ml of 20 percent aqueous sulfuric acid was heated at reflux for 48hours. The mixture was cooled to room temperature and extracted with2×50 ml of ether. The ether extracts were combined and washed with 25 mlof saturated sodium bicarbonate solution and 25 ml of saturated NaClsolution and dried (MgSO₄). The solvent was removed in vacuo and theresidue purified by flash column chromatography (silica: 2% ethylacetate in hexanes) followed by kugelrohr distillation to give the titlecompound as a clear oil.

PMR (CDCl₃); & 1.810 (6H, s), 1.282 (6H, s), 1.234 (2H, s), 7.047 (1H,dd, J˜2 Hz, J˜8.8 Hz) 7.114 (1H, d J˜8.8 Hz) 7.16 (1H, d, J˜2 Hz).

2,2,4,4 Tetramethyl-7-trimethylsilyl-ethynyl-thiochroman (Compound 37)

A solution of 3 g (10.5 mmol) of 2,2,4,4 tetramethyl-7-bromo-thiochroman(Compound 36) and 5.16 g (52.6 mmol) of trimethylsilylacetylene in 5 mlof triethylamine was placed in a heavy walled glass tube and degassedunder nitrogen. The mixture was then treated, under nitrogen, with 184mg (0.966 mmol) of cuprous iodide and 368 mg (0.524 mmol) of bis(triphenylphosphine) palladium (II) chloride, the reaction mixture wasdegassed again and placed under nitrogen and the tube was sealed. Themixture was heated at 60° C. for 24 hours, cooled to room temperature,and then filtered through celite. The solvent was removed in vacuo andthe residue purified by flash column chromatography (silica; 100%hexanes) to give the title compound as a pale yellow solid.

PMR (CDCl₃); & 0.22 (9H, s), 1.35 (6H, s), 1.38 (6H, s), 1.93 (2H, s),7.16 (1H, dd, J˜8.1 Hz, J˜1.74 Hz), 7.24 (1H, d, J˜1.74 Hz) 7.30 (1H,J˜8.1 Hz)

2,2,4,4-Tetramethyl-7-ethynyl-thiochroman (Compound 38)

To a solution of 1.04 g (3.4 mmole) of 2,2,4,4tetramethlyl-7-trimethylsilylethynyl thiochroman (Compound 37) in 3 mlof isopropanol was added 5 ml of ethanolic KOH solution. The reactionmixture was stirred at room temperature for 24 hours and the alcohol wasthen removed in vacuo. The residue was extracted with ether (20 ml) andthe combined ether layers were washed with water (15 ml) and saturatedNaCl solution (20 ml) and dried (MgSO₄). The solvent was removed invacuo and the residue purified by kugelhohr distillation to give thetitle compound as a clear oil.

PMR (CDCl₃); & 1.38 (6H, s), 1.42 (6H, s), 1.95 (2H, s), 3.02 (1H, s),7.20 (1H, dd, J˜8.1 Hz, 2.1 Hz), 7.29 (1H, d, J˜2.1 Hz), 7.34 (1H, d,J˜8.1 Hz)

Ethyl-4-(2,2,4,4-tetramethyl-7-thiochromanyl) ethynyl-benzoate (Compound3)

A solution of 390 mg (1.7 mmol) of 2,2,4,4 tetramethyl-7-ethynyl-thiochroman (Compound 38) and 552 mg (2.0 mmol) of ethyl 4-iodobenzoate in 3ml of triethylamine was placed in a heavy walled glass tube and degassedfor 0.25 hours under nitrogen. The mixture was treated with 18 mg (0.256mmol) of bis (triphenylphosphine) palladium (II) chloride and 8 mg(0.042 mmol) of cuprous iodide under nitrogen and stirred for 5 minutes.The mixture was treated again with the same amounts of bis(triphenylphosphine) palladium II chloride and cuprous iodide, and themixture was degassed again. The tube was then sealed and the reactionmixture was heated at 45° C. for 70 hours and then cooled to roomtemperature. The reaction mixture was filtered through celite and thesolvent was removed under vacuum. The residue was purified by flashcolumn chromatography (silica; 1%/Ethylacetate in hexane) to give thetitle compound as a white solid.

PMR (CDCl₃): & 1.37-1.43 (15H, m), 1.96 (2H, s), 4.39 (2H, q, J˜7.0 Hz),7.26 (1H, dd, J˜8.2 Hz, 1.8 Hz), 7.34 (1H, d, J˜1.8 Hz), 7.37 (1H, d,J˜8.2 Hz), 7.56 (2H, d, J ˜8.0 Hz), 8.02 (2H, d, J˜8.0 Hz).

3-Bromophenyl 3,3-dimethyl acrylate (Compound 39)

To an ice-cooled suspension of 4 g (100 mmol) of sodium hydride (60% inmineral oil) in 50 ml of dry THF was added dropwise a solution of 15.7 g(90.7 mmol) of 3-bromo phenol in 25 ml of dry THF. The mixture wasstirred at 0 degrees C. for 0.5 hours and then treated with a solutionof 10.65 g (90.0 mmol) of dimethyl acryloyl chloride in 30 ml of dryTHF. The mixture was allowed to warm to room temperature and stirred for24 hours. The reaction mixture was poured onto 200 ml of ice watercontaining 3 ml of glacial acetic acid. The mixture was extracted with2×250 ml ether and the combined ether extracts were washed with 200 mlof water and 100 ml saturated NaCl solution and dried (MgSO₄). Thesolvent was removed in vacuo and the residue purified by kugelrohrdistillation to give the title compound as a clear oil.

PMR (CDCl₃): & 2.02 (3H, s), 2.28 (3H, s), 5.94 (1H, broad s), 7.06-7.12(1H, m), 7.28 (1H, t, J˜8.0 Hz), 7.34 (1H, t, J˜2.0 Hz), 7.37-7.42 (1H,m).

3-Bromo-2-(1,1,3-Trimethyl-3-hydroxybutyl)phenol (Compound 41)

To a stirred, ice-cooled suspension of 21 g (158 mmol) of aluminumchloride in 200 ml of methylene chloride was added slowly a solution of23.74 g (93.1 mmol) of 5-bromo-phenyl-3,3-dimethyl acrylate (Compound39) in 100 ml of methylene chloride. The mixture was warmed to roomtemperature and stirred for 52 hours. The mixture was poured into amixture of ice and brine and the organic layer was separated. Theaqueous layer was extracted with 2×100 ml ether. The organic extractswere combined and washed with 2×250 ml of water and 50 ml of saturatedNaCl solution and dried (MgSO₄). The solvent was removed in vacuo andthe residue was partially purified by flash column chromatography,(silica; 5% ethyl acetate/hexane) to give impure4,4-dimethyl-7-bromo-2-oxochroman (Compound 40) as a yellow oil whichwas used in the next step without further purification. To an ice-cooledsolution of 10 g of this impure 4,4,dimethyl-7-bromo-2-oxochroman(Compound 40) in 200 ml of dry THF was added under argon 39.2 ml of 3.0Mmethyl magnesium chloride (117.6 mmol) in THF. The reaction mixture wasallowed to warm to room temperature and stirred for 5 hours. Thereaction mixture was then poured into ice water containing 2 ml ofsulfuric acid and the organic layer was separated. The aqueous layer wasextracted with 200 ml of ether. The organic extracts were combined andwashed with 200 ml of water and 200 ml of brine and dried (MgSO₄). Thesolvent was removed in vacuo and the residue purified by flash columnchromatography (silica; 10% ethylacetate/hexanes) to give the titlecompound as a pale yellow oil.

PMR (CDCl₃): & 0.98 (6H, s), 1.36 (6H, s), 2.15 (2H, s), 6.82 (1H, d,J˜1.9 Hz), 6.86 (1H, dd, J˜8.3 Hz, 1.9 Hz), 7.04 (1H, d, J˜8.3 Hz).

2,2,4,4-tetramethyl-7-bromochroman (Compound 42)

A mixture of 5.42 (18.9 mmol) of 3-bromo-2(1,1,3trimethyl-3-hydroxy-butyl) phenol (Compound 41) and 50 ml of 20 percentaqueous sulfuric acid was heated at reflux for 24 hours. The reactionmixture was cooled to room temperature and treated with 100 ml of ether.The organic layer was separated and the aqueous layer was extracted with50 ml of ether. The ether extracts were combined and washed with 100 mlof water and 100 ml saturated NaCl solution and dried (MgSO₄). Thesolvent was removed in vacuo and the residue was purified by Kugelrohrdistillation to give the impure title compound as a pale yellow oil.

PMR (CDCl₃): & 1.22 (6H, s), 1.24 (6H, s), 1.72 (2H, s), 6.87 (1H, d,J˜2.0 Hz), 6.92 (1H, dd, J˜8.3 Hz, 2.0 Hz), 7.02 (1H, d, J˜8.3 Hz) .

2,2,4,4-Tetramethyl-7-trimethylsilylethynyl-chroman (Compound 43)

A solution of 2 g (7.4 mmol) of 2,2,4,4 tetramethyl-7-bromochroman(Compound 42) and 3.63 g (37.0 mmol) of trimethylsilylacetylene in 5 mlof triethylamine was placed in a heavy walled glass tube and degassedunder nitrogen. The mixture was then treated, under nitrogen, with 130mg (0.6826 mmol) of cuprous iodide and 260 mg (0.3704 mmol) of bis(triphenyl phosphine) palladium (II) chloride. The reaction mixture wasdegassed again and placed under nitrogen and the tube was sealed. Themixture was heated to 60 degrees C. for 24 hours and then cooled to roomtemperature and filtered through celite. The solvent was removed invacuo and the residue purified by flash column chromatography (silica;2% ethyl acetate/hexane) to give the title compound as a pale yellowsolid.

PMR (CDCl₃): & 0.23 (9H, s), 1.32 (12H, s), 1.82 (2H, s), 6.92 (1H, d,J˜1.6 Hz) 7.00 (1H, dd, J˜8.6 Hz, 1.6 Hz) , 7.19 (1H, J˜8.6 Hz)

2,2,4,4-tetramethyl-7-ethynyl chroman (Compound 44)

To a solution of 1.16 g (4.1 mmol) of2,2,4,4-tetramethyl-7-trimethylsilylethynyl-chroman (Compound 43) in 3ml of isopropanol was added 5 ml of ethanolic KOH solution. The reactionmixture was stirred at room temperature for 24 hours and the alcohol wasthen removed under vacuum. The residue was extracted with 2×10 ml ofether and the combined ether extracts were washed with 15 ml of waterand 20 ml of saturated NaCl solution and then dried (MgSO₄). The solventwas removed in vacuo and the residue purified by Kugelrohr distillationto give the title compound as a white crystalline solid.

PMR (CDCl₃): & 1.33 (6H, s), 1.34 (6H, s), 1.83 (2H, s), 2.99 (1H, s),6.94 (1H, d, J˜1.7 Hz), 7.04 (1H, dd, J˜8.0 Hz, 1.7 Hz), 7.21 (1H, d,J˜8.0 Hz).

Ethyl-4-(2,2,4,4-tetramethyl-7-chromanyl)-ethynyl-benzoate (Compound 4)

A solution of 270 mg (1.26 mmol) of 2,2,4,4 tetramethyl-7-ethynylchroman (Compound 44) and 420 mg (1.52 mmol) of ethyl 4-iodobenzoate in4 ml of triethylamine was placed in a heavy walled glass tube anddegassed under nitrogen for 15 minutes. The mixture was treated with 6mg (0.0315 mmol) of cuprous iodide and 13 mg (0.0185 mmol) ofbis(triphenylphosphine) palladium (II) chloride under nitrogen, andstirred for 5 minutes. The mixture was treated again with the sameamounts of bis (triphenyl phosphine) palladium II chloride and cuprousiodide. The mixture was degassed again and the tube was sealed. Thereaction mixture was heated to 45° for 70 hours and then cooled to roomtemperature. The reaction mixture was filtered through celite and thesolvent was removed under vacuum. The residue was purified by flashcolumn chromatography (silica; 1% ethyl acetate in hexanes) to give thetitle compound as a white solid.

PMR (CDCl₃): & 1.32 (6H, s), 1.33 (6H, s), 1.40 (3H, t, J ˜7.2 Hz), 1.84(2H, s), 4.38 (2H, d, J˜7.2 Hz), 7.00 (1H, d, J˜1.4 Hz), 7.09 (1H, dd,J˜7.9 Hz, 1.4 Hz), 7.25 (1H, d, J ˜7.9 Hz), 7.56 (2H, d, J˜8.3 Hz), 8.02(2H, J˜8.3 Hz).

3-Bromophenyl-3-methyl-but-2-enylsulfide (Compound 45)

A solution of 25 g (132 mmol) of 3-bromothiophenol in 100 ml of acetonewas heated to reflux and then treated with 5.56 g (139 mmol) of powderedNaOH. The mixture was refluxed for a further 0.5 hour. The refluxingmixture was then treated with a solution of 19.7 g (132 mmol) of1-bromo-3-methyl-2-butene in 30 ml of acetone and refluxed for a further1.5 hours. The mixture was cooled and then solvent was removed in-vacuo.The residue was extracted with ether and the ether extract was washedwith dilute NaOH solution, water, and saturated NaCl solution andthereafter dried (CaCl₂). After evaporation of the solvent, the residuewas purified by vacuum distillation to give the title compound as awhite crystalline solid.

PMR (CDCl₃): & 1.61 (3H, s), 1.72 (3H, s), 3.52 (2H, d, J ˜7.8 Hz), 5.27(1H, t, J˜7.8 Hz) 7.10 (1H, t, J˜7.8 Hz), 7.21 (1H, dt, J˜7.8 Hz, J˜1.8Hz), 7.27 (1H, dt, J˜7.8 Hz, J˜1.8 Hz), 7.44 (1H, t, J˜1.8 Hz).

4,4,Dimethyl-7-trimethylsilylethynyl-Thiochroman (Compound 47)

To 3.63 g (14 mmol) of 3-bromophenyl-3-methyl-but-2-enyl sulfide(Compound 45) was added 15 g of a 1:10 P₂ O₅, MeSO₃ H mixture, andstirred at room temperature for 4 hours. The mixture was treated withcool water followed by boiling water. The mixture was stirred for 10minutes and cooled to room temperature. The reaction mixture was thenextracted with ether and the combined ether extracts were washed withwater and then saturated NaCl solution and dried (CaCl₂). The solventwas removed in vacuo and the residue purified by Kugelrohr distillation(140 degrees C./0.2 mm) to give impure 4,4-dimethyl-7-bromo-thiochroman(Compound 46) as a pale yellow solid. This was used in the next stepwithout further purification. A solution of 2.03 g of this impure 4,4dimethyl-7-bromo thiochroman (Compound 46) in 2 ml of triethylamine wasplaced in a heavy-walled tube and degassed and then treated under argonwith 3.8 g (38.9 mmol) of trimethylsilylacetylene a powdered mixture of100 mg of bis (triphenylphosphine) palladium (II) chloride and 50 mg ofcuprous iodide. The reaction mixture was degassed again, then placedunder argon and the tube was sealed. The mixture was heated at 60° C.for 12 hours. The mixture was cooled to room temperature and thenfiltered through celite. The solvent was removed in vacuo and theresidue purified by flash chromatography (silica; hexanes) to give thetitle compound as a yellow oil.

PMR (CDCl₃): & 0.22 (9H, s), 1.3 (6H, s), 1.91-1.98 (2H, t, J˜6.0 Hz),2.99-3.2 (2H, t, J˜6.0 Hz) 7.09 (1H, dd, J˜1.8, J˜8.2 Hz) 7.20 (1H, d,J˜1.8 Hz) 7.26 (1H, d, J˜8.2 Hz).

Ethyl-4-(4,4-dimethyl-7-thiochromanyl)-ethynyl-benzoate (Compound 1)

To a solution of 1 g (3.6 mmol) of4,4-dimethyl-7-trimethylsilylethynyl-thio-chroman (Compound 47) in 10 mlof isopropyl alcohol was added 5 ml of 1N KOH solution. The reactionmixture was stirred at room temperature for 18 hours and the isopropanolwas then removed under vacuum. The residue was extracted with ether andthe ether extracts were combined and washed with dilute HCl solution,water and saturated NaCl solution, and were thereafter dried (MgSO₄).The solvent was removed in vacuo to give impure4-4-dimethyl-7-ethynyl-thiochroman (Compound 48) as a pale yellow oil.This mixture was used in the next step without further purification. Asolution of 281 mg of this impure 4,4-dimethyl-7-ethynylthiochroman(Compound 48) and 384 mg (1.4 mmol) of ethyl 4-iodo-benzoate in 1 ml oftriethylamine was placed in a heavy walled glass tube and degassed undernitrogen. The mixture was treated with 60 mg of cuprous iodide and 30 mgof bis (triphenyl phosphine) palladium (II) chloride. The reactionmixture was degassed again under nitrogen, and the tube was sealed. Thereaction mixture was stirred at room temperature for 18 hours. Thesolvent was removed under high vacuum and the residue purified by flashcolumn chromatography (silica; 3% EtOAC/hexane) to give the titlecompound as an off-white solid.

PMR (CDCl₃): & 1.32 (6H, s), 1.40 (3H, t, J˜7.1 Hz), 1.92-1.99 (2H, m),2.99-3.06 (2H, m), 4.38 (2H, q, J˜7.1 Hz, 7.17 (1H, dd, J˜8.2 Hz, 1.7Hz), 7.28 (1H, d, J˜1.7 Hz), 7.34 (1H, d, J˜8.2 Hz), 7.55 (2H, d, J˜8.5Hz), 8.01 (2H, d, J˜8.5 Hz).

4-[4-4-Dimethyl-7-thiochromanyl)-ethynyl] benzoic acid (Compound 2)

To 150 mg (0.428 mmol) ofethyl-4-(4,4-dimethyl-7-thiochromanyl-ethynyl-benzoate (Compound 1) wasadded 5 ml of ethanolic KOH solution and the reaction mixture wasstirred at room temperature for 24 hours. The ethanol was removed invacuo and the residue was taken up in 3 ml of water and 3 ml of ether.The layers were separated and the aqueous layer was washed with ether.The aqueous layer was acidified to Ph=2 with 1N HCl and was extractedwith 2×20 ml of ether. The combined ether extracts were washedsuccessively with water and saturated NaCl solution and then dried(MgSO₄). The solvent was removed in vacuo to give the title compound asa white solid.

PMR (CDCl₃): & 1.30 (6H, s), 1.91-1.97 (2H, m), 2.99-3.04 (2H, m), 7.14(1H, dd, J˜8.1 Hz, 1.7 Hz), 7.24 (1H, d, J˜1.7 Hz), 7.32 (1H, d, J˜8.1Hz), 7.52 (2H, d, J˜8.3 Hz), 7.99 (2H, d, J˜8.3 Hz).

4-(2,2,4,4-Tetramethyl-7-thiochromanyl)-ethynyl-benzoic acid (Compound49)

To 99 mg (0.262 mmol) of ethyl-4-(2,2,4,4-tetramethyl-7-thiochromanyl)ethynyl-benzoate (Compound 3) was added 5 ml of an ethanolic KOHsolution. The reaction mixture was stirred at room temperature for 48hours and the solvent was then removed in vacuo. The residue was takenup with water and ether and the layers were separated. The aqueous layerwas acidified to Ph˜2 with 1N HCl and extracted with ether. The etherlayer was then washed with water and saturated sodium chloride and thendried (MgSo₄). The solvent was removed in vacuo to give the titlecompound as a white solid PMR (CDCl₃): & 1.40 (6H, s), 1.42 (6H, s),1.98 (2H, s), 7.23-7.29 (2H, m), 7.43 (1H, d, J˜8.6 Hz), 7.57 (2H, d,J˜8.5 Hz), 8.01 (2H, d, J˜8.5 Hz).

4- (2,2,4,4-tetramethyl-7-chromanyl)-ethynyl benzoic acid (Compound 50 )

To 207.2 mg (0.572 mmol) of ethyl-4-(2,2,4,4-tetramethyl-7-chromanyl)ethynyl-benzoate (Compound 4) was added 5 ml of ethanolic KOH solution.The reaction mixture was stirred at room temperature for 48 hours andthe solvent was then removed in vacuo. The residue was taken up withwater and ether and the layers were separated. The aqueous layer wasacidified to Ph˜2 with 1N HCl and extracted with ether. The ether layerwas then washed with water and saturated sodium chloride and then dried(MgSO₄). The solvent was removed in vacuo to give the title compound asa pale yellow solid.

PMR (CDCl₃): & 1.37 (12H, s), 1.87 (2H, s), 6.95 (1H, d, J˜1.6 Hz), 7.09(1H, dd, J˜8.0 Hz, 1.6 Hz), 7.30 (1H, d, J ˜8.0 Hz), 7.57 (2H, d, J˜8.3Hz), 8.02 (2H, d, J˜8.3 Hz).

What is claimed is:
 1. A compound of the formula ##STR14## where X is Sor O; R₁, R₂, R₄ and R₅ independently are hydrogen or lower alkyl of 1to 3 carbons, and R₃ is hydrogen or lower alkyl;A is lower branchedchain alkyl having 2 to 6 carbons, cycloalkyl having 3 to 6 carbons,alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2to 6 carbons and 1 or 2 triple bonds, (CH₂)_(n) and where n is aninteger from 0-5; R₆ is hydrogen, lower alkyl, lower alkenyl or lowercycloalkyl having 1 to 6 carbons, or halogen; and B is COOH or apharmaceutically acceptable salt thereof, COOR₈, COONR₉ R₁₀, where R₈ isan alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10carbons, or R₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independentlyare hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl groupof 5 to 10 carbons, or phenyl or lower alkylphenyl.
 2. A compound ofclaim 1 where X is S.
 3. A compound of claim 2 where A is (CH₂)_(n) andn is 0, 1, or
 2. 4. A compound of claim 3 where R₄ is H and R₅ is loweralkyl.
 5. A compound of claim 3 where R₄ is the same alkyl group as R₅.6. A compound of claim 3 where R₄ is lower alkyl and R₅ is lower alkyland R₄ and R₅ are different.
 7. A compound of claim 3 where R₄ and R₅are both hydrogen.
 8. A compound of claim 1 where X is O.
 9. A compoundof claim 8 where A is (CH₂)_(n) and n is 0, 1, or
 2. 10. A compound ofclaim 9 where R₄ is H and R₅ is lower alkyl.
 11. A compound of claim 9where R₄ is lower alkyl and R₅ is lower alkyl and R₄ and R₅ aredifferent.
 12. A compound of claim 9 where R₄ is the same alkyl group asR₅.
 13. A compound of claim 10 where R₄ and R₅ are both H.
 14. Apharmaceutical composition comprising one or more compounds set forth inclaim 1, the composition including a pharmaceutically acceptableexcipient.
 15. A compound of the formula ##STR15## where R₁, R₂, R₄ andR₅ independently are hydrogen or lower alkyl of 1 to 3 carbons and R₃ ishydrogen or lower alkyl;A is lower branched chain alkyl having 2 to 6carbons, cycloalkyl having 3 to 6 carbons, alkenyl having 2 to 6 carbonsand 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triplebonds, (CH₂)_(n) where n is an integer between 0 to 5; and B is COOH ora pharmaceutically acceptable salt thereof, COOR₈, COONR₉ R₁₀, where R₈is an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5 to 10carbons, or R₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independentlyare hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl groupof 5 to 10 carbons, or phenyl or lower alkylphenyl.
 16. A compound ofclaim 15 wherein A is (CH₂)_(n) and n is
 0. 17. A compound of claim 16where R₁ -R₅ are independently H or methyl.
 18. A compound of claim 17where B is COOC₂ H₅.
 19. The compound of claim 18 where R₃ is H and R₁,R₂, R₄ and R₅ are methyl.
 20. The compound of claim 18 where R₁, R₂ aremethyl and R₃, R₄ and R₅ are hydrogen.
 21. A compound of claim 17 whereB is COOH.
 22. A compound of claim 21 where R₃ is H and R₁, R₂, R₄ andR₅ are methyl.
 23. A compound of claim 21 where R₁ and R₂ are methyl andR₃, R₄ and R₅ are H.
 24. The compound of claim 16 where B is COOH or apharmaceutically acceptable salt thereof, R₁, R₂ are methyl, and R₃, R₄and R₅ are hydrogen.
 25. A compound of the formula ##STR16## where R₁,R₂, R₄ and R₅ independently are hydrogen or lower alkyl of 1 to 3carbons and R₃ is hydrogen or lower alkyl;A is lower branched chainalkyl having 2 to 6 carbons, cycloalkyl having 3 to 6 carbons, alkenylhaving 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6carbons and 1 or 2 triple bonds, (CH₂)_(n) where n is an integer between0 to 5, and B is COOH or a pharmaceutically acceptable salt thereof,COOR₈, COONR₉ R₁₀, where R₈ is an alkyl group of 1 to 10 carbons, or acycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or loweralkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or phenyl orlower alkylphenyl.
 26. A compound of claim 25 where A is (CH₂)_(n) and nis
 0. 27. A compound of claim 26 where B is COOC₂ H₅.
 28. The compoundof claim 27 where R₃ is hydrogen, R₁, R₂, R₄ and R₅ are methyl.
 29. Acompound of claim 26 where B is COOH.
 30. A compound of claim 29 whereR₃ is hydrogen, R₁, R₂, R₄ and R₅ are methyl.